Blood-brain barrier: emerging trends on transport models and new-age strategies for therapeutics intervention against neurological disorders

Abstract

The integrity of the blood-brain barrier (BBB) is essential for normal central nervous system (CNS) functioning. Considering the significance of BBB in maintaining homeostasis and the neural environment, we aim to provide an overview of significant aspects of BBB. Worldwide, the treatment of neurological diseases caused by BBB disruption has been a major challenge. BBB also restricts entry of neuro-therapeutic drugs and hinders treatment modalities. Hence, currently nanotechnology-based approaches are being explored on large scale as alternatives to conventional methodologies. It is necessary to investigate the in-depth characteristic features of BBB to facilitate the discovery of novel drugs that can successfully cross the barrier and target the disease effectively. It is imperative to discover novel strategies to treat life-threatening CNS diseases in humans. Therefore, insights regarding building blocks of BBB, activation of immune response on breach of this barrier, and various autoimmune neurological disorders caused due to BBB dysfunction are discussed. Further, special emphasis is given on delineating BBB disruption leading to CNS disorders. Moreover, various mechanisms of transport pathways across BBB, several novel strategies, and alternative routes by which drugs can be properly delivered into CNS are also discussed.

Keywords: BBB dysfunction; Blood–brain barrier; Central nervous system; Drug delivery; Nanoparticles; Neurological diseases.

Fig. 1

Blood–brain barrier (BBB) building blocks: endothelial cell (ECs), basement membrane, pericytes, astrocytes, adherent junction (AT) and tight junctions (TJ)

Fig. 2

Breaching of the BBB and entry of effectors of the immune system. Rupturing of the blood vessel is followed by leukocyte release; cytokines like IL-1, IFN-γ, TNF-α and chemokines are also secreted by endothelial cells (ECs) joined together via tight junctions (TJs). Vessel rupture promotes release of reactive oxygen species (ROS) and matrix metalloproteinases (MMPs), resulting in basement membrane disintegration. The figure has been adapted from [57]

Fig. 3

Activation of TNF-α and TGF-β Signaling by albumin during BBB breakdown induces rapid upregulation of genes associated to inflammation considering NF-ĸβ pathways and complimentary cascades, cytokines and chemokines (IL-6, CcL-2, CcD-7, Cd14) [86]. The pro-inflammatory molecules secreted by microglia and astrocytes contribute to voltage fluctuation in different parts of the brain. The figure is adapted from [87]

Fig. 4

Schematic diagram showing mutations in several genes i.e. presenilin-1(PSEN1), presenilin-2 (PSEN2), amyloid-beta precursor protein (APP), apolipoprotein (APOE3), and apolipoprotein 4 (APOE4) related to increase risk of neurological disorders. Alzheimer’s disease (AD) is caused by mutations in the above genes and also by hyperphosphorylation of tau proteins in the distal part of axons in neuronal cells results in NFTs and cell death

Fig. 5

Reduced levels of TJs due to BBB dysfunction lead to pericyte degeneration causing infiltration of antibodies (IgG), intercellular adhesion molecule (ICAM-1/2/vascular cell adhesion molecules (VCAM), thrombin, plasminogen, haemoglobin (Hb) and iron (II) released from RBCs further produce ROS in the matrix, toxic for motor neurons in case of ALS. This figure is adapted from [66]

Fig. 6

Key pathological characteristics of Parkinson’s disease (PD) are depicted. These include cell death in the Substantia Nigra and Lewy bodies [aggregation of α-synuclein (α-syn),] affecting dopamine releasing neurons. BBB breakdown leads to accumulation of various blood components, leading to production of ROS and thus affecting dopaminergic astrocytes and neurons in case of PD. This figure is adapted from [118]

Fig. 7

Transport pathways/routes allowing accessibility across BBB. A Passive transcellular diffusion/dispersion: Passive diffusion of solutes across BBB is facilitated by higher solubility of lipids. B Active efflux of penetrating solutes out of ECs is mediated via efflux carriers C Modulation of TJs affects the paracellular diffusional pathway permeability. D Carrier-mediated transcytosis system transport several essential polar molecules into CNS like glucose, nucleosides, etc. E Macromolecules such as proteins and regulatory molecules, across the cerebral endothelium can be directed via receptor mediated transcytosis. F Paracellular pathway is used by small water-soluble molecules for movement across CNS. G Adsorptive mediated transcytosis is induced by cationic macromolecules which aid movement across BBB. The idea of the figure is adapted from [164]

Fig. 8

Various novel strategies for effective drug delivery into the brain: invasive techniques, non-invasive techniques and other alternative approaches adapted from [170]

Fig. 9

Lipid-based nanoparticles for treating neurodisorders are illustrated A liposomes, B solid lipid nanoparticle (SLN); Polymeric nanoparticles, C polymeric miscelles, D dendrimers and E illustrating the major properties of nanoparticles that influence systemic delivery and transport through BBB. NPs have the ability to deliver drugs into cells by covalently bounding, entrapping or adsorbing them. They can be of different shapes (rod-like, spherical, or cube) and charges (positive, zwitterionic, or negative). NPs can be natural such as proteins (albumin), chitosan or synthetic NPs which are made from commonly used polymers like poly (lactic acid) (PLA), poly (lactic-co-glycolic acid) (PLGA), or from inorganic agents like gold, silica, or alumina. Also, these NPs can be functionalized using different types of ligands. (i) efficient in mediating protein adsorption [Polysorbate-80 (P-80)], (ii) direct interaction with BBB (transferrin proteins, peptides or antibodies), (iii) increasing hydrophobicity (amphiphilic peptides), and (iv) ability to increase blood circulation (PEG). The figure is adapted from [235]